The major aims of this project have been accomplished through the establishment of a large community-based family study of adult probands who participate in comprehensive clinical and biologic assessments followed by comparable evaluations of their adult and child relatives. Recruitment of probands and evaluation of relatives are near completion and analyses of the findings are underway. To date, about 550 probands and about 1000 of their relatives have completed the study, including over 150 children between the ages of 7-17. Approximately 500 individuals have also been evaluated at the NIH Clinical Center. Probands represent a large range of disorders including mood, anxiety, sleep, migraine, and cardiovascular in addition to controls. We are now completing interviews with relatives who had not previously participated in the study. During the past year, we have continued to recruit new probands and family members. We are also following up the original sample, repeating interviews, ecological momentary assessment (EMA), actigraphy, and clinic measures, to assess the stability of these measures over time and track their relationship with emerging mental and medical illness in probands and family members, especially offspring. We have completed collection and genotyping of DNA samples, and we plan to conduct statistical genetic analyses during the coming year. We have completed analyses of the clinical validity of our interview, Diagnostic Interview for Affective and Anxiety Spectrum (DIAS), as compared to the Structured Clinical Interview for DSM Disorders (SCID), (Nakamura et al, in preparation). Results showed overall good concordance between the SCID and DIAS, with the DIAS frequently eliciting more information especially in regards to anxiety disorders. We have conducted extensive analyses of the clinical and biomarker phenotypes of familial aggregation data during the past year. We have also investigated comorbidity and co-aggregation of mood disorder subtypes with attention deficit hyperactivity disorder (ADHD), insomnia, cardiovascular risk factors, chronotype, and temperament (Iorfino et al, under review). Findings indicated that temperamental traits tapping anxiety are highly familial, but these traits do not appear to constitute manifestations of the same underlying diathesis as anxiety and mood disorders. Likewise, we found that ADHD does not appear to share a common underlying diathesis with bipolar disorder (BPD), whereas insomnia may reflect a common risk factors underlying mania and atypical depression. We have also devoted substantial effort to harmonize the measures and data sets from the Lausanne Family Study with the NIMH Family Study and plan to conduct joint analyses of the data on youth. We have analyzed joint data on comorbidity and co-aggregation of suicide and mental disorders, and shown that social anxiety disorder (SAD) is associated with suicide attempts in families (Ballard et al, submitted). We have nearly completed analyses on additional biomarkers that were collected on both probands and relatives. We found that bipolar 1 (BPI) disorder was characterized by lower average and greater variability in motor activity, and that those with BPD have greater reactivity across homeostatic regulatory systems of activity, sleep, mood and energy (Shou et al, 2017; Scott et al, 2017). Analyses of olfactory thresholds and detection revealed that people with BPI and major depression have deficits in odor identification, particularly attributable to the subgroup with psychotic symptoms (Kamath et al, under revision). Using ecological momentary sampling, we further showed that people with BPD have greater reactivity to positive events, whereas variability in mood and anxiety appears to be a trait marker of people with a history of mood disorders in general (Lamers et al, under review). We have employed a novel statistical technique to study the stability of emotional and attention states using fragmentation models (Johns et al, under review). We have now developed new EMA scripts that will be used in several sites to increase the generalizability of the samples and the power of these analyses. We are also analyzing sleep patterns and disorders as well as physical activity and their associations with mood disorder subtypes. Although there are no differences between people with mood disorder subtypes on the startle domains, we found that social anxiety is strongly associated with habituation and baseline startle. These startle domains are also highly familial. Therefore, we plan to follow up these findings by extending the sample to include more people with SAD and to recruit more family members. In summary, we have now confirmed with our preliminary analyses that people with BPI disorder differ from those with other subtypes of mood disorders and/or controls in terms of variability of motor activity, rhythms of sleep and activity, greater cross-domain reactivity, and greater autonomic reactivity. People with SAD tend to have greater reactivity to startle than those with mood disorders or controls. The major shift in the emphasis of the study is to follow up the sample to evaluate the stability of the clinical phenomena and potential biomarkers and their association with developmental manifestations of mood disorders and their core components. Publications in preparation/submitted/under review: -Nakamura E, et al. Validation of the Diagnostic Interview for Affective and Anxiety Spectrum Disorders (DIAS). -Iorfino F, et al. Familial aggregation of anxiety disorder subtypes and temperamental traits in the NIMH Family Study of Affective Spectrum Disorders. -Ballard E, et al. Familial aggregation of suicidal behavior and c-aggregation with mood and anxiety disorder subtypes. -Kamath V, et al. Olfactory processing in bipolar disorder, major depression, and anxiety. -Lamers F, et al. Mood variability and reactivity in mood disorder subtypes. -Johns J, et al. Fragmentation as a novel measure of stability in normalized trajectories of mood and attention assessed by electronic diaries. Public Health Impact: Integration of the clinical, neuropsychological and psychophysiological measures within families will render an in-depth analysis of the biological mechanisms crucial for mood and anxiety disorders and their underlying diatheses. This will not only lead to a better understanding of these conditions and assist in identifying common genetic mechanisms, but may also lead to the development of novel treatment options and possible strategies for prevention and early intervention in those with elevated risk for these conditions. Future Plans: The initial findings of our study have major implications for etiology, treatment, course and nosology of mood and anxiety disorders. However, the work requires replication in larger samples, re-assessment to examine stability of the findings, and collaboration with other sites to cover the full range of the spectrum of mood disorders, and increase the power of the study. We are now working to increase the number of probands with BPD and SAD in the study and are conducting comprehensive examinations of relatives, with a particular focus on youth ages 12-30. We continue to follow up the families already enrolled in the project to examine the stability of findings, re-consent participants for sharing of genetic data, and repeat the mobile technologies measures to examine their fluctuation over time. Based on the findings from study analyses, we plan to design and pilot interventions that stabilize regulation of activity, sleep and other daily rhythms in this and other samples. We also plan to establish a collaborative network of affiliated studies of community, high risk and clinical samples of youth with common measures of mood and motor activity.